The risk of developing metastatic disease in breast cancer patients is traditionally predictable based on the number of positive axillary lymph nodes, complemented with additional clinicopathological factors. However, since lymph node-negative patients have a 20–30% probability of developing metastatic disease, lymph node information alone is insufficient to accurately assess individual risk. Molecular approaches, such as multigene expression panels, analyze a set of cancer-related genes that more accurately predict the early risk of metastasis and the treatment response. Here, we present N-Myc downstream-regulated gene 4 (NDRG4) epigenetic silencing as a mechanistic biomarker of metastasis in ductal invasive breast tumors. While aberrant NDRG4 DNA hypermethylation is significantly associated with the development of metastatic disease, downregulation of NDRG4 transcription and protein expression is functionally associated with enhanced lymph node adhesion and cell mobility. Here, we show that epigenetic silencing of NDRG4 modulates integrin signaling by assembling β1-integrins into large punctate clusters at the leading edge of tumor cells to promote an “adhesive switch,” decreasing cell adhesion to fibronectin and increasing cell adhesion and migration towards vitronectin, an important component of human lymph nodes. Taken together, our functional and clinical observations suggest that NDRG4 is a potential mechanistic biomarker in breast cancer that is functionally associated with metastatic disease.

传统上，乳腺癌患者发生转移性疾病的风险是根据腋窝淋巴结阳性数量并辅以其他临床病理因素来预测的。然而，由于淋巴结阴性患者有 20-30% 的可能性发生转移性疾病，仅淋巴结信息不足以准确评估个体风险。分子方法，例如多基因表达组，分析一组与癌症相关的基因，可以更准确地预测转移的早期风险和治疗反应。在这里，我们提出 N-Myc 下游调节基因 4 (NDRG4) 表观遗传沉默作为导管浸润性乳腺肿瘤转移的机械生物标志物。虽然异常的 NDRG4 DNA 高甲基化与转移性疾病的发展显着相关，但 NDRG4 转录和蛋白表达的下调在功能上与增强的淋巴结粘附和细胞流动性相关。在这里，我们发现NDRG4的表观遗传沉默通过将β1-整合素组装成肿瘤细胞前缘的大点状簇来调节整合素信号传导，以促进“粘附开关”，减少细胞对纤连蛋白的粘附并增加细胞粘附和向玻连蛋白的迁移，人体淋巴结的重要组成部分。综上所述，我们的功能和临床观察表明 NDRG4 是乳腺癌的潜在机制生物标志物，在功能上与转移性疾病相关。